Mitofusin agonists to prevent Charcot-Marie-Tooth disease 2A

丝裂霉素激动剂预防腓骨肌萎缩症 2A

• 批准号: 9901962
• 负责人: Gerald W. Dorn
• 金额: $ 25.44万
• 依托单位: MITOCHONDRIA IN MOTION, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901962
• 关键词: Adolescent; Affect; Age; Agonist; Alleles; American; Amyotrophic Lateral Sclerosis; Atrophic; Binding Proteins; Biological Availability; Biotechnology; Blinded; Brain; Capital Financing; Caregivers; Caring; Cell model; Cells; Charcot-Marie-Tooth Disease; Chemicals; Child; Childhood; Controlled Study; DNA Sequence Alteration; Data; Defect; Degenerative Disorder; Diagnosis; Disease; Distal; Drug Kinetics; FDA approved; Family; Fibroblasts; Forearm; Funding; Genes; Genetic; Goals; Growth; Hand; Hand Strength; Healthcare; Histology; Hour; Human; Huntington Disease; Intramuscular; Investigation; Lead; Leg; Life; Limb structure; Metabolism; Mitochondria; Modification; Molecular Conformation; Motion; Mus; Muscular Atrophy; Muscular Dystrophies; Mutation; Natural regeneration; Nerve; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; Neuropathy; Onset of illness; Patients; Peripheral Nerves; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Plasma; Preparation; Prevention; Probability; Proteins; Quality of life; Randomized; Rare Diseases; Resources; Safety; Small Business Technology Transfer Research; Technology; Toxic effect; Universities; Validation; Variant; Washington; Wheelchairs; arm; biomarker identification; cell motility; commercialization; disability; disease-causing mutation; drug metabolism; efficacy study; first-in-human; fitness; foot; grasp; humanized mouse; improved; in vivo; inhibitor/antagonist; medical schools; mitochondrial dysfunction; mitochondrial fitness; motility disorder; mouse model; mutant; nerve injury; nervous system disorder; neuromuscular; novel drug class; pre-clinical; prevent; programs; rare genetic disorder; repaired; research and development; response to injury; sciatic nerve; skeletal; small molecule; tissue culture; trafficking; young adult

Mitofusin agonists to prevent Charcot-Marie-Tooth disease 2A Gerald W Dorn II, MD Mitochondria in Motion, Inc. Washington University in St Louis School of Medicine Abstract: Charcot-Marie-Tooth (CMT) disease type 2A is an incurable, primarily pediatric, autosomal dominant neuromuscular degenerative disease caused by mutations in the mitofusin (MFN) 2 gene. There are currently no disease-altering treatments. Mitochondria in Motion, Inc. will develop and produce investigational first-in-class small molecule mitofusin agonists, under an FDA approved IND, to treat CMT2A and other neurological diseases. Mitofusin agonists enhance mitochondrial fitness, metabolism, and trafficking within cells, thus improving homeostatic functioning and injury-responses of neurons adversely impacted by MFN2 genetic mutations. Here, we hypothesized that activating endogenous, genetically normal MFN2 and MFN1 will reverse dominant inhibition by CMT2A MFN2 mutants of neuronal mitochondrial fusion and trafficking, thus delaying or preventing CMT2A-induced neuromuscular degeneration. Our immediate goals are to refine our lead mitofusin agonist for in vivo administration (SA#1) and to provide proof-of-concept for in vivo mitofusin agonist efficacy in a mouse model of aggressive CMT2A (SA#2) to support our preclinical data in CMT2A patient- derived cells. We will fill an unmet healthcare need and build a commercial enterprise to serve the ~10,000 Americans with CMT2A and the >200,000 Americans suffering from other neurodegenerative diseases characterized by mitochondrial degeneration, including CMT type 1, amyotrophic lateral sclerosis, and Huntington’s disease. Our deliverable in this 1 year Phase I STTR will be a mitofusin agonist(s) ready for STTR Phase II IND-enabling studies in CMT2A and validation in an expanded number of orphan diseases, in preparation for anticipated first-in-human trials.

预防夏科-玛丽-图斯病的丝裂霉素激动剂 Gerald W Dorn II，医学博士 运动中的线粒体公司 华盛顿大学圣路易斯医学院 摘要：2A型Charcot-Marie-Tooth(CMT)病是一种不治之症，主要 儿童常染色体显性遗传性神经肌肉退行性疾病由 丝裂原蛋白(MFN)2基因突变。目前还没有改变疾病的方法 治疗。运动中的线粒体公司将开发和生产研究用的 一流的小分子丝裂原激动剂，根据FDA批准的IND，以 治疗CMT2A和其他神经系统疾病。丝裂霉素激动剂增强 线粒体的适合性、新陈代谢和细胞内的运输，从而改善 神经细胞的稳态功能和损伤反应 Mfn2基因突变。在这里，我们假设激活内源性， 基因正常的Mfn2和Mfn1将逆转CMT2A的显性抑制 Mfn2突变体的神经元线粒体融合和运输，从而延迟或 预防CMT2A诱导的神经肌肉变性。我们的近期目标 是提炼我们的主要丝裂原激动剂用于体内给药(SA#1)，并 为丝裂原激动剂在小鼠模型中的体内疗效提供概念验证 积极的CMT2A(SA#2)来支持我们在CMT2A患者中的临床前数据- 派生的细胞。我们将满足未得到满足的医疗保健需求，并建立一个商业 企业将通过CMT2A和&gt；20万为大约10,000名美国人提供服务 患有其他神经退行性疾病的美国人的特征是 线粒体变性，包括CMT 1型，肌萎缩侧索硬化症， 和亨廷顿氏症。我们在这项为期1年的第一阶段STTR中的交付内容将是 丝裂霉素激动剂(S)准备用于CMT2a和CMT2a的STTRII期IND使能研究 在更多的孤儿疾病中进行验证，为 预计将进行首例人体试验。